The fate of double positive thymocytes is dictated by the strength and duration of the interaction between TCR and self peptide-MHC complex presented on the cortical thymic epithelial cells. A weak interaction results in positive selection and survival signals which rescue DP thymocytes from death by neglect. Positive selection is critical for immune function, as this is the process by which a repertoire of T cells bearing useful TCR specificities is produce. However little is known about the transcriptional control of positive selection. We found that the transcription factor BCL11B controls early steps of positive selection, as removal results in attenuated TCR signaling and failure of positive selection. In addition, in the absence of BCL11B DP thymocytes have reduced survival even in the absence of TCR signaling, demonstrating that BCL11B is a major player in the control of survival of DP thymocytes. Supporting our hypothesis that BCL11B is critical for positive selection and survival of DP thymocytes we have evidence that BCL11B controls expression of genes associated with positive selection and survival of DP thymocytes. In addition, in the absence of BCL11B starting with DP stage of T cell development the reduced number of peripheral BCL11B-deficient T lymphocytes present an activated phenotype and mice develop wasting disease and colitis. Conditional removal of BCL11B in mature T cells also results in increased number of activated CD4+ T cells. These results support the hypothesis that BCL11B regulates mature CD4+ T lymphocytes. Using conditional and inducible mouse system and biochemical studies we propose to investigate the mechanisms by which BCL11B controls positive selection and survival of DP thymocytes through transcriptional control of gene expression. In addition we propose to determine the role of BCL11B in conventional and T regulatory CD4+ T cells. Public Health Relevance Statement: The results of these studies will contribute significantly to a molecular understanding of positive selection and survival of DP thymocytes, which both play a crucial role in generation of the appropriate T cells for an adequate immune response. In addition, these studies will contribute to understanding transcriptional program of effector CD4+ T and CD4+ T regulatory cells, and have important implications for autoimmune diseases.